Project Summary Social isolation (SI) predicts morbidity and mortality from a multitude of health conditions, including cancer, cardiovascular disease, and stroke. Patients with high levels of social support or large social networks exhibit more rapid and extensive functional recovery after stroke than socially isolated individuals, and the impact of these factors appears to be greater in elderly women. Social interaction overcomes the detrimental effects of SI by promoting adaptive behaviors and favorable neuroendocrine responses to biological stressors. Despite the huge impact of SI on post-stroke recovery, no study has attempted to mitigate the detrimental effects of isolation on neurobehavioral outcomes using target-based approaches. MicroRNAs (miRNAs) are short non-coding RNAs that are emerging as a powerful intervention tool for many diseases including stroke. They regulate a broad spectrum of biological pathways through fine-tuning of protein expression levels and altering gene expression levels. They have the ability to concurrently target multiple effectors of pathways involved in disease pathology. Very recent studies have found that microRNAs mediate many aspects of social interaction, leading us to hypothesize that miRNA regulation is involved in post-stroke pathology after SI. Preliminary studies have found that expression of several miRNAs including miR-181c-5p and miR-124-5p, which are involved in regulation of inflammation, long term potentiation and neurotrophin signaling, are modulated by post-stroke isolation in aged mice. In this proposal we will determine which miRNAs are differentially expressed in aged male and female mice isolated after stroke and determine if blocking (with genetic deletion or antagomirs) or enhancing (mimics) these target miRNA modulates their effects. The overall goal of this proposal is to determine if manipulation of target miRNAs can improve functional recovery after stroke in aged animals subjected to SI, a major risk factor for poor recovery.